胃癌致死率逐年上升,侵袭转移是其死亡的主要原因,阐明调控胃癌侵袭转移的分子及机制具有重要意义.既往研究表明,血管活性肠肽（VIP）作为微环境中的重要调节因子,在胃癌患者血清及癌组织中高水平表达并与胃癌侵袭转移密切相关,然而VIP调控胃癌侵袭转移的机制不清.Ca2+离子作为一重要的第二信使,已被证实在多种肿瘤细胞的迁移及侵袭转移中发挥重要调控作用.我们前期预实验发现VIP可通过TRPV4通道促胃癌细胞外Ca2+内流增加,而TRPV4抑制剂可抑制VIP促胃癌迁移及侵袭的作用.据此,我们推测“VIP可激活TRPV4通道开放促胃癌细胞外Ca2+内流增加,通过TRPV4/Ca2+信号参与胃癌侵袭转移的调控".本课题拟通过分子生物学、钙测定及膜片钳等技术,阐明VIP促TRPV4通道激活的分子及功能机制,并证实TRPV4/Ca2+信号在胃癌侵袭转移中的重要作用,为探寻胃癌侵袭转移的防治靶标提供依据.

The mortality of gastric cancer (GC) increased year by year, and the invasion and metastasis have been the main cause of death. Therefore, it is of great importance to elucidate the molecule and mechanisms invovled in GC invasion and metastasis. The previous study demonstrated that vasoactive intestinal peptide (VIP), as an important regulatory factor in microenvironment, was upregulated in serum and tumor tissues of GC patients, and the high level of expression was positively correlated with invasion and metastasis of GC. However, the mechanisms of VIP in GC invasion and metastasis are still unknown. Calcium is an important second messanger, which has been proved to play an important role in promoting migration and invasion of cancer cells. Our preliminary experiments showed that VIP could increase the calcium influx in GC cells through the TRPV4 channel, and TRPV4 inhibitor could inhibit VIP-induced migration and invasion in GC cells. Thus, we hypothesize that VIP might activate TRPV4 channel to increase the calcium influx in GC cells and promote GC invasion and metastasis through TRPV4/Ca2+ signaling. This proposal will elucidate the molecular and functional mechanisms of VIP activating TRPV4 channel and regulating calcium signaling using molecular biology, calcium analysis and patch clamp. Moreover, we will further uncover the role of TRPV4/Ca2+ signaling in VIP-induced GC invasion and metastasis, which will provide the evidence for exploring the prevention target of GC metastasis.